Phenyl bicyclic methyl azetidine derivatives as sphingosine-1 phosphate receptors modulators

ABSTRACT

The present invention relates to novel phenyl bicyclic methyl azetidine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

RELATED APPLICATION

This application is a divisional application of United StatesNon-Provisional patent application Ser. No. 13/446,143, filed Apr. 13,2012, which claims the benefit of U.S. Provisional Application Ser. No.61/475,346, filed Apr. 14, 2011, all of which are incorporated here byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel phenyl bicyclic methyl azetidinederivatives, processes for preparing them, pharmaceutical compositionscontaining them and their use as pharmaceuticals as modulators ofsphingosine-1-phosphate receptors. The invention relates specifically tothe use of these compounds and their pharmaceutical compositions totreat disorders associated with sphingosine-1-phosphate (S1P) receptormodulation.

BACKGROUND OF THE INVENTION

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular diseases.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

SUMMARY OF THE INVENTION

We have now discovered a group of novel compounds which are potent andselective sphingosine-1-phosphate modulators. As such, the compoundsdescribed herein are useful in treating a wide variety of disordersassociated with modulation of sphingosine-1-phosphate receptors. Theterm “modulator” as used herein, includes but is not limited to:receptor agonist, antagonist, inverse agonist, inverse antagonist,partial agonist, partial antagonist.

This invention describes compounds of Formula I, which havesphingosine-1-phosphate receptor biological activity. The compounds inaccordance with the present invention are thus of use in medicine, forexample in the treatment of humans with diseases and conditions that arealleviated by S1P modulation.

In one aspect, the invention provides a compound having Formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the geometrical isomers, enantiomers, diastereoisomers,tautomers, zwitterions and pharmaceutically acceptable salts thereof:

wherein:

represents a single bond

or a double bond

A is substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted C₅₋₈ cycloalkyl,substituted or unsubstituted C₅₋₈ cycloalkenyl or hydrogen;R² is hydrogen, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl;R³ is hydrogen, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl;R⁴ is OPO₃H₂, carboxylic acid, PO₃H₂, substituted or unsubstituted C₁₋₆alkyl, —S(O)₂H, —P(O)MeOH, —P(O)(H)OH or OR¹⁰;R⁵ is hydrogen, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl;R⁶ is hydrogen, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl;R⁷ is hydrogen, OR¹⁰ or substituted or unsubstituted C₁₋₃ alkyl;R⁸ is hydrogen or substituted or unsubstituted C₁₋₃ alkyl;R⁹ is hydrogen or substituted or unsubstituted C₁₋₃ alkyl;R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₃ alkyl;

L¹ is O, S, NH or CH₂;

L² is O, S, NH, a direct bond or CH₂;a is 0 or 1;b is 0, 1, 2 or 3;c is 1, 2 or 3; andd is 1, 2 or 3; with the provisoswhen a is 1 then

represents

andwhen a is 0 then R¹ is O, S, NH, or CH₂.

In another aspect, the invention provides a compound having Formula Iwherein:

represents a single bond

or a double bond

A is substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted C₅₋₈ cycloalkyl,substituted or unsubstituted C₅₋₈ cycloalkenyl or hydrogen;R² is hydrogen, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl;R³ is hydrogen, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl;R⁴ is OPO₃H₂, carboxylic acid, PO₃H₂, substituted or unsubstituted C₁₋₆alkyl, —S(O)₂H, —P(O)MeOH, —P(O)(H)OH or OR¹⁰;R⁵ is hydrogen, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl;R⁶ is hydrogen, halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl;R⁷ is hydrogen, OR¹⁰ or substituted or unsubstituted C₁₋₃ alkyl;R⁸ is hydrogen or substituted or unsubstituted C₁₋₃ alkyl;R⁹ is hydrogen or substituted or unsubstituted C₁₋₃ alkyl;R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₃ alkyl;

L¹ is O, S, NH or CH₂;

L² is O, S, NH, a direct bond or CH₂;a is 1;b is 0, 1, 2 or 3;c is 1, 2 or 3; andd is 1, 2 or 3; and

represents

In another aspect, the invention provides a compound having Formula Iwherein:

represents a double bond

A is hydrogen;R² is hydrogen;R³ is hydrogen;R⁴ is carboxylic acid;R⁵ is hydrogen;R⁶ is hydrogen;R⁷ is hydrogen;

L¹ is CH₂;

L² is a direct bond;a is 1;b is 0;c is 2 or 3;d is 3; and

represents

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 6 carbon atoms. One methylene(—CH₂—) group, of the alkyl can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C₃₋₆cycloalkyl. Alkyl groups can be substituted by halogen, hydroxyl,cycloalkyl, amino, non-aromatic heterocycles, carboxylic acid,phosphonic acid groups, sulphonic acid groups, phosphoric acid.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, preferably 3 to 5 carbon atomsderived from a saturated cyclic hydrocarbon. Cycloalkyl groups can bemonocyclic or polycyclic. Cycloalkyl can be substituted by 1 to 3 C₁₋₃alkyl groups or 1 or 2 halogens.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, preferably 3 to 6 carbon atomsderived from a saturated cycloalkyl having one double bond. Cycloalkenylgroups can be monocyclic or polycyclic. Cycloalkenyl groups can besubstituted by 1 to 3 C₁₋₃ alkyl groups or 1 or 2 halogens.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by 1 to 2 C₁₋₃ alkyl.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or non-saturated,containing at least one heteroatom selected form O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be saturated or non-saturated. Theheterocyclic ring can be interrupted by a C═O; the S heteroatom can beoxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclicring moieties can be substituted by hydroxyl, C₁₋₃ alkyl or halogens.Usually, in the present case, heterocyclic groups are 5 or 6 memberedrings. Usually, in the present case, heterocyclic groups are pyridine,furan, azetidine, thiazol, thiophene, oxazol, pyrazol.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen, which can be substituted by halogenatoms or by C₁₋₃ alkyl groups. Usually aryl is phenyl. Preferredsubstitution site on phenyl are meta and para positions.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula“—S═O”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—(O)P(O)(OH)₂”.

The term “boronic acid”, as used herein, represents a group of formula“—B(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, such as for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid and the like; or an organic acid such as for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaricacid, maleic acid, oxalic acid, tartaric acid, succinic acid, malicacid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric,methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like(Handbook of Pharmaceutical Salts, P.Heinrich Stahal& Camille G. Wermuth(Eds), Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

The base addition salt form of a compound of Formula I that occurs inits acid form can be obtained by treating the acid with an appropriatebase such as an inorganic base, for example, sodium hydroxide, magnesiumhydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like;or an organic base such as for example, L-Arginine, ethanolamine,betaine, benzathine, morpholine and the like. (Handbook ofPharmaceutical Salts, P.Heinrich Stahal& Camille G. Wermuth (Eds),Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the sphingosine-1-phosphate receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of sphingosine-1-phosphatereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byS1P modulation: not limited to the treatment of diabetic retinopathy,other retinal degenerative conditions, dry eye, angiogenesis and wounds.

Therapeutic utilities of S1P modulators are ocular diseases, such as butnot limited to: wet and dry age-related macular degeneration,angiogenesis inhibition, diabetic retinopathy, retinopathy ofprematurity, retinal edema, geographic atrophy, glaucomatous opticneuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemicsyndrome, prevention of inflammation-induced fibrosis in the back of theeye, various ocular inflammatory diseases including uveitis, scleritis,keratitis, and retinal vasculitis; or systemic vascular barrier relateddiseases such as but not limited to: various inflammatory diseases,including acute lung injury, its prevention, sepsis, tumor metastasis,atherosclerosis, pulmonary edemas, and ventilation-induced lung injury;or autoimmune diseases and immunosuppression such as but not limited to:rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatorybowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis,ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury,contact hypersensitivity, atopic dermititis, and organ transplantation;or allergies and other inflammatory diseases such as but not limited to:urticaria, bronchial asthma, and other airway inflammations includingpulmonary emphysema and chronic obstructive pulmonary diseases; orcardiac protection such as but not limited to: ischemia reperfusioninjury and atherosclerosis; or wound healing such as but not limited to:scar-free healing of wounds from cosmetic skin surgery, ocular surgery,GI surgery, general surgery, oral injuries, various mechanical, heat andburn injuries, prevention and treatment of photoaging and skin ageing,and prevention of radiation-induced injuries; or bone formation such asbut not limited to: treatment of osteoporosis and various bone fracturesincluding hip and ankles; or anti-nociceptive activity such as but notlimited to: visceral pain, pain associated with diabetic neuropathy,rheumatoid arthritis, chronic knee and joint pain, tendonitis,osteoarthritis, neuropathic pains; or central nervous system neuronalactivity in Alzheimer's disease, age-related neuronal injuries; or inorgan transplant such as renal, corneal, cardiac or adipose tissuetransplant.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation ofsphingosine-1-phosphate receptors. Such methods can be performed, forexample, by administering to a subject in need thereof a therapeuticallyeffective amount of at least one compound of the invention, or anycombination thereof, or pharmaceutically acceptable salts, hydrates,solvates, crystal forms and individual isomers, enantiomers, anddiastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of ocular disease, wet and dry age-relatedmacular degeneration, angiogenesis inhibition, diabetic retinopathy,retinopathy of prematurity, retinal edema, geographic atrophy,glaucomatous optic neuropathy, chorioretinopathy, hypertensiveretinopathy, ocular ischemic syndrome, prevention ofinflammation-induced fibrosis in the back of the eye, various ocularinflammatory diseases including uveitis, scleritis, keratitis, andretinal vasculitis; or systemic vascular barrier related diseases,various inflammatory diseases, including acute lung injury, itsprevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas,and ventilation-induced lung injury; or autoimmune diseases andimmunosuppression, rheumatoid arthritis, Crohn's disease, Graves'disease, inflammatory bowel disease, multiple sclerosis, Myastheniagravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renalischemia/perfusion injury, contact hypersensitivity, atopic dermititis,and organ transplantation; or allergies and other inflammatory diseases,urticaria, bronchial asthma, and other airway inflammations includingpulmonary emphysema and chronic obstructive pulmonary diseases; orcardiac protection, ischemia reperfusion injury and atherosclerosis; orwound healing, scar-free healing of wounds from cosmetic skin surgery,ocular surgery, GI surgery, general surgery, oral injuries, variousmechanical, heat and burn injuries, prevention and treatment ofphotoaging and skin ageing, and prevention of radiation-inducedinjuries; or bone formation, treatment of osteoporosis and various bonefractures including hip and ankles; or anti-nociceptive activity,visceral pain, pain associated with diabetic neuropathy, rheumatoidarthritis, chronic knee and joint pain, tendonitis, osteoarthritis,neuropathic pains; or central nervous system neuronal activity inAlzheimer's disease, age-related neuronal injuries; or in organtransplant such as renal, corneal, cardiac or adipose tissue transplant.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists ofsphingosine-1-phosphate receptors. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of sphingosine-1-phosphate receptors. Such methods canbe performed, for example, by administering to a subject in need thereofa pharmaceutical composition containing a therapeutically effectiveamount of at least one invention compound. As used herein, the term“therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of Formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The synthetic schemes set forth below, illustrate howcompounds according to the invention can be made.

Those skilled in the art will be able to routinely modify and/or adaptthe following scheme to synthesize any compounds of the inventioncovered by Formula I.

The following abbreviations are used in the general schemes:

TFA trifluoroacetic acid

NaOH sodium hydroxide

t-BuLi tert-butyl lithium

B(OMe)₃ trimethoxyborane

K₂CO₃ potassium carbonate

Tol toluene

Et₃SiH triethylsilane

EtOH ethanol

Pd(PPh)₄ Tetrakis(triphenylphosphine)palladium(0)

To a solution of appropriately substituted bromophenone in ethanol isadded sodium hydroxide followed by a solution of aldehyde. The reactionmixture is stirred at room temperature and then an extraction with waterand ethyl acetate is performed. The ene-one formed is reduced in thepresence of trifluorocaetic acid and triethylsilane to afford thecorresponding saturated arylbromide. This arylbromide will be reactedwith the desired bromoquinolone aldehyde or bromo naphthylmethylesterafter treated with t-butyllithium and trimethylborate. This aldehydereacts with an azetidine in the presence of sodium cyanoborohydride togive the crude compound of Formula I. Trituration or columnchromatography gave the corresponding compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hydrogen ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 8; and Intermediates andreagent names used in the examples were generated with software such asChem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5SP1.

In general, characterization of the compounds is performed according tothe following methods:

NMR spectra are recorded on 300 and/or 600 MHz Varian and acquired atroom temperature. Chemical shifts are given in ppm referenced either tointernal TMS or to the solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by columnchromatography (Auto-column) on an Teledyne-ISCO CombiFlash with asilica column, unless noted otherwise.

The following abbreviations are used in the examples:

CDCl₃ deuterated chloroform

MPLC medium pressure liquid chromatography

THF tetrahydrofuran

RT room temperature

MgSO₄ magnesium sulfate

LiCl lithium chloride

HCl hydrochloric acid

Those skilled in the art will be able to routinely modify and/or adaptthe following schemes to synthesize any compound of the inventioncovered by Formula I.

Some compounds of this invention can generally be prepared in one stepfrom commercially available literature starting materials.

Example 1 Intermediate 1 5-(4-hexylphenyl) quinoline-8-carbaldehyde

To a solution of 1-bromo-4-hexylbenzene (CAS 237033-22-2) (500 mg, 1.7mmol) in THF (15 mL) at −78° C. was added t-butyllithium (1.7 M inpentane, 2.0 mL) slowly dropwise. After stirring at −78° C. for 1 h,trimethyl borate (0.39 mL, 3.46 mmol) was added. The reaction mixturewas warmed at RT over 2 h. After stirring at RT for 15 min, the reactionmixture was quenched with saturated solution of ammonium chloride andextracted with ethyl acetate. The combined organic layers were washedwith HCl (10% solution), brine, and dried (MgSO₄), filtered, andconcentrated under reduced pressure and gave 415 mg of the correspondingboronic acid as colorless solid.To a solution of the resulting boronic acid (4.07 mg, 1.5 mmol) and5-bromoquinoline-8-carbaldehyde (CAS 885267-41-4) (292 mg, 1.4 mmol) intoluene (30 mL) were added potassium carbonate (436 mg, 3.15 mmol) andLiCl (67 mg) with stirring. After bubbling with Argon for 10 min,tetrakis(triphenylphosphine)palladium(0) (36 mg) was added and heated at95° C. for 16 h. After the reaction mixture was cooled at RT, it wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, and dried (MgSO₄), filtered, andconcentrated under reduced pressure. The residue was purified by MPLC(15% ethyl acetate in hexanes) and gave 320 mg of Intermediate 1 ascolorless solid.

¹H NMR (300 MHz, CDCl₃) δ 11.50 (s, 1H), 9.06 (dd, J=1.61, 3.96 Hz, 1H),8.37 (d, J=7.33 Hz, 2H), 7.65 (d, J=7.33 Hz, 1H), 7.47 (dd, J=4.25, 8.64Hz, 1H), 7.33-7.40 (m, 4H), 2.72 (t, J=7.60 Hz, 2H), 1.65-1.75 (m, 2H),1.31-1.46 (m, 6H), 0.91 (t, J=6.70 Hz, 3H).

Example 2 Compound 11-{[5-(4-hexylphenyl)quinolin-8-yl]methyl}azetidine-3-carboxylic acid

To a suspension of Intermediate 1 (261 mg, 0.82 mmol) in methanol (12mL) was added 3-azetidinecarboxylic acid (87 mg, 0.86 mmol). Afterstirring at room temperature for 2 h, sodium cyanoborohydride (62 mg,0.99 mmol) was added. After stirring at room temperature for 4 h, themethanol was removed. Purification by MPLC (0-100% ethyl acetate inhexanes) gave Compound I (181 mg, 33%) as colorless solid.

¹H NMR (600 MHz, CDCl₃) δ 8.91 (dd, J=1.61, 3.96 Hz, 1H), 8.27 (dd,J=1.76, 8.51 Hz, 1H), 8.05 (d, J=7.34 Hz, 1H), 7.49 (d, J=7.34 Hz, 1H),7.36 (dd, J=4.11, 8.51 Hz, 1H), 7.29-7.34 (m, 4H), 4.93 (s, 2H),4.39-4.42 (m, 2H), 4.14 (t, J=9.10 Hz, 2H), 3.34-3.39 (m, 1H), 2.69 (t,J=8.51 Hz, 2H), 1.67-1.72 (m, 2H), 1.33-1.43 (m, 6H), 0.90-0.93 (m, 3H).

Biological Data

Compounds were synthesized and tested for S1P1 activity using the GTPγ³⁵S binding assay. These compounds may be assessed for their ability toactivate or block activation of the human S1P1 receptor in cells stablyexpressing the S1P1 receptor.

GTP γ³⁵S binding was measured in the medium containing (mM) HEPES 25, pH7.4, MgCl₂ 10, NaCl 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nMGTP γ³⁵S, and 5 μg membrane protein in a volume of 150 μl. Testcompounds were included in the concentration range from 0.08 to 5,000 nMunless indicated otherwise. Membranes were incubated with 100 μM5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDPfor 10 min on ice. Drug solutions and membrane were mixed, and thenreactions were initiated by adding GTP γ³⁵S and continued for 30 min at25° C. Reaction mixtures were filtered over Whatman GF/B filters undervacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25,pH7.4, MgCl₂ 10 and NaCl 100). Filters were dried and mixed withscintillant, and counted for ³⁵S activity using a β-counter.Agonist-induced GTP γ³⁵S binding was obtained by subtracting that in theabsence of agonist. Binding data were analyzed using a non-linearregression method. In case of antagonist assay, the reaction mixturecontained 10 nM S1P1 in the presence of test antagonist atconcentrations ranging from 0.08 to 5000 nM.

Compound1-{[5-(4-Hexylphenyl)quinolin-8-yl]methyl}azetidine-3-carboxylic acidshows an EC₅₀ of 1550 nM at the S1P1 receptor from GTP γ³⁵S.

What is claimed is:
 1. A method of treating an immunosuppressantdisorder associated with the sphingosine-1-phosphate receptormodulation, wherein the immunosuppressant disorder is selected from:rheumatoid arthritis, psoriasis, atherosclerosis, autoimmune uveitis,dry eye, inflammatory bowel diseases, atopic allergy, atopic dermatitis,contact dermatitis, multiple sclerosis, Sjogren's syndrome and organtransplant rejection, in a mammal in need thereof, which comprisesadministering to a mammal in need thereof, a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundrepresented by Formula I or a pharmaceutically acceptable salt thereof:

wherein:

represents a single bond

or a double bond

A is substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted C₅₋₈ cycloalkyl,substituted or unsubstituted C₅₋₈ cycloalkenyl or hydrogen; R¹ is O, S,NH, CH or CH₂; R² is hydrogen, halogen, —OC₁₋₃ alkyl, substituted orunsubstituted C₁₋₃ alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl; R³ is hydrogen,halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl, CN,C(O)R⁷, NR⁸R⁹ or hydroxyl; R⁴ is OPO₃H₂, carboxylic acid, PO₃H₂,substituted or unsubstituted C₁₋₆ alkyl, —S(O)₂H, —P(O)MeOH, —P(O)(H)OHor OR¹⁰; R⁵ is hydrogen, halogen, —OC₁₋₃ alkyl, substituted orunsubstituted C₁₋₃ alkyl, CN, C(O)R⁷, NR⁸R⁹ or hydroxyl; R⁶ is hydrogen,halogen, —OC₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkyl, CN,C(O)R⁷, NR⁸R⁹ or hydroxyl; R⁷ is hydrogen, OR¹⁰ or substituted orunsubstituted C₁₋₃ alkyl; R⁸ is hydrogen or substituted or unsubstitutedC₁₋₃ alkyl; R⁹ is hydrogen or substituted or unsubstituted C₁₋₃ alkyl;R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₃ alkyl; L¹ is O, S,NH or CH₂; L² is O, S, NH, a direct bond or CH₂; a is 0 or 1; b is 0, 1,2 or 3; c is 1, 2 or 3; and d is 1, 2 or 3; with the provisos when a is1 then

represents

and when a is 0 then R¹ is O, S, NH, or CH₂.
 2. The method according toclaim 1, wherein the mammal is a human.
 3. The method according to claim1, wherein:

represents a single bond


4. The method according to claim 1, wherein: a is
 1. 5. The methodaccording to claim 1, wherein:

represents a double bond


6. The method according to claim 1, wherein:

represents


7. The method according to claim 1, wherein:

represents a double bond

A is hydrogen; R² is hydrogen; R³ is hydrogen; R⁴ is carboxylic acid; R⁵is hydrogen; R⁶ is hydrogen; R⁷ is hydrogen; L¹ is CH₂; L² is a directbond; a is 1; b is 0; c is 2 or 3; d is 3; and

represents


8. The method according to claim 1, wherein: A is hydrogen.
 9. Themethod according to claim 1, wherein the compound is:1-{[5-(4-hexylphenyl)quinolin-8-yl]methyl}azetidine-3-carboxylic acid.